GnRH receptors (GnRH-R) have been found in various malignancies, including prostate cancer (PCa). They mediate the direct antitumor effects of GnRH analogs. Nevertheless, few reports concern drug-induced modulation of GnRH-R levels. In this study, we investigated GnRH-R expression in androgen-sensitive (LNCaP) and -insensitive (PC-3) PCa cells treated for 4 and 6 days with a GnRH agonist (Leuprorelin acetate, LA, 10(-11) or 10(-6) M), Dihydrotestosterone (DHT, 10(-9) M), Cyproterone acetate (CA, 10(-7) M), and Epidermal growth factor (EGF, 10 ng/ml), either alone or combined. The RT-PCR analysis showed no variation in GnRH-R mRNA levels of both treated LNCaP and PC-3 cells. On the contrary, immunoblotting indicated that in LNCaP and PC-3 cells, LA upregulated membrane GnRH-R expression (up to 92%). In androgen-sensitive cells, DHT induced a GnRH-R increase (up to 119%) always comparable to that occurring in the presence of CA. GnRH-R upregulation by LA/DHT or CA/DHT association was similar to that promoted by the single agents. In PC-3 cells, EGF upregulated GnRH-R (up to 110%). A prolonged treatment (for 12 days) determined a greater EGF-induced increase in GnRH-R levels (142%). Lower (or no) receptor enhancement occurred when LA and EGF were associated. Our findings indicate that LA post-transcriptionally upregulates its own membrane receptor in androgen-sensitive and -insensitive PCa cells, counteracting the receptor enhancement produced by DHT and EGF. The effects, obtained with a relatively long and continuous treatment, may have implications in the choice of therapy modality with GnRH analogs and may render the receptor a novel therapeutic target, particularly in hormone-refractory PCa.

Angelucci, C., Lama, G., Iacopino, F., Ferracuti, S., Bono, A. V., Millar, R. P., Sica, G., GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors, <<ENDOCRINE>>, 2009; 36 (1): 87-97 [http://hdl.handle.net/10807/28731]

GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors

Angelucci;Cristiana; Lama;Gina; Iacopino;Robert P.; Sica
2009

Abstract

GnRH receptors (GnRH-R) have been found in various malignancies, including prostate cancer (PCa). They mediate the direct antitumor effects of GnRH analogs. Nevertheless, few reports concern drug-induced modulation of GnRH-R levels. In this study, we investigated GnRH-R expression in androgen-sensitive (LNCaP) and -insensitive (PC-3) PCa cells treated for 4 and 6 days with a GnRH agonist (Leuprorelin acetate, LA, 10(-11) or 10(-6) M), Dihydrotestosterone (DHT, 10(-9) M), Cyproterone acetate (CA, 10(-7) M), and Epidermal growth factor (EGF, 10 ng/ml), either alone or combined. The RT-PCR analysis showed no variation in GnRH-R mRNA levels of both treated LNCaP and PC-3 cells. On the contrary, immunoblotting indicated that in LNCaP and PC-3 cells, LA upregulated membrane GnRH-R expression (up to 92%). In androgen-sensitive cells, DHT induced a GnRH-R increase (up to 119%) always comparable to that occurring in the presence of CA. GnRH-R upregulation by LA/DHT or CA/DHT association was similar to that promoted by the single agents. In PC-3 cells, EGF upregulated GnRH-R (up to 110%). A prolonged treatment (for 12 days) determined a greater EGF-induced increase in GnRH-R levels (142%). Lower (or no) receptor enhancement occurred when LA and EGF were associated. Our findings indicate that LA post-transcriptionally upregulates its own membrane receptor in androgen-sensitive and -insensitive PCa cells, counteracting the receptor enhancement produced by DHT and EGF. The effects, obtained with a relatively long and continuous treatment, may have implications in the choice of therapy modality with GnRH analogs and may render the receptor a novel therapeutic target, particularly in hormone-refractory PCa.
Inglese
Angelucci, C., Lama, G., Iacopino, F., Ferracuti, S., Bono, A. V., Millar, R. P., Sica, G., GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors, <<ENDOCRINE>>, 2009; 36 (1): 87-97 [http://hdl.handle.net/10807/28731]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/28731
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